The major objective of our research proposal is to study the mechanism by which glucagon or cyclic-AMP-induced metabolic changes are blocked in the liver. Specifically, we are interested in studying the relationship between the glucagon and cyclic-AMP-induced changes in ion redistribution, membrane hyperpolarization and the subsequent increase in glucose production. Thus, we are studying the effects of agents which are interfering or changing by themselves ionic distribution on the glucagon-induced increase in gluconeogenesis. The effects of tetracaine, Na-free and high K perfusate agents and experimental conditions in which glucagon-induced ion fluxes and metabolic parameters are blocked are being studied further. Because one of the primary effects of glucagon is an efflux of calcium from the liver, the effects of the calcium ionophore A23 on ion fluxes and hepatic metabolism is investigated. The experimental system employed in the above studies is a hemoglobin-free in situ perfused liver system.